(Applicant's Abstract) Most cases of asthma begin during the first years of life. This suggests that a significant proportion of the risk for the development of asthma can be attributed to complex gene by environment interactions occurring during these early years. Understanding the developmental alterations of the immune system in early life that are associated with the subsequent development of asthma, is essential to designing a strategy for primary and secondary prevention of the disease. In this SCOR proposal we will integrate molecular, immunologic, genetic, genomic, and epidemiologic approaches to study the immune, genetic, and environmental interactions that occur at the beginning of asthma. In Project 1 we explore the gene by environment interactions that may be involved in the apparent protective effect of an increased microbial burden in early life on the development of early allergic sensitization and asthma. A population sample of children living in rural areas of Europe and in whom exposure to indoor endotoxin has been assessed will be studied. Known or newly discovered polymorphisms in genes coding for the main components of the endotoxin response system will be assessed and related to endotoxin exposure and asthma-related outcomes. In Project 2, the genetic and immune factors that explain the strong and independent relation between atopic dermatitis (eczema) in early life and the subsequent development of asthma will be explored. It is well known that most children who will go on to develop asthma show Th2-deviated responses to local aeroallergens very early in life, but not all children who do show such responses develop the disease. Project 3 will explore the complex molecular mechanisms that determine if a Th2-deviated response will result in the synthesis of IgG4, IgE or both in humans. Finally, we have recently described five new polymorphisms in the promoter region of the CD14 gene. We have shown that these polymorphisms are associated with total serum IgE levels in school children. Project 4 will explore the biology of novel proximal and distant regulatory elements of the CD14 gene and will thus provide new insights on the mechanisms by which the innate immune response may influence the susceptibility to early allergies and asthma. Our SCOR offers a unique opportunity to study in a comprehensive manner the way in which environmental factors and genetic background influence the maturation of the immune system during the initial phases of the asthma process.